Glucocorticoid receptor signaling in bone cells

Glucocorticoids are used for treating a wide range of diseases including inflammation and autoimmune disorders. However, there are drawbacks, primarily due to adverse effects on bone cells resulting in osteoporosis. Evidence indicates that the ratio of benefits to adverse effects depends greatly on glucocorticoid receptor (GR)-mediated mechanisms. Delineating GR-mediated signaling in bone cells will allow development of selective GR ligands/agonists (SEGRAs), which would dissociate the positive therapeutic (anti-inflammatory) effects from the negative effects on the skeleton. The present review provides an in-depth account of the current knowledge of GR-mediated transcriptional regulation of specific genes and proteins engaged in the proliferation, differentiation, and apoptosis of bone cells (osteoblasts, osteocytes, osteoclasts). We hope this knowledge will advance research in the development of SEGRAs with improved benefit/risk ratios. Glucocorticoids are used for treating a wide range of diseases including inflammation and autoimmune disorders. However, there are drawbacks, primarily due to adverse effects on bone cells resulting in osteoporosis. Evidence indicates that the ratio of benefits to adverse effects depends greatly on glucocorticoid receptor (GR)-mediated mechanisms. Delineating GR-mediated signaling in bone cells will allow development of selective GR ligands/agonists (SEGRAs), which would dissociate the positive therapeutic (anti-inflammatory) effects from the negative effects on the skeleton. The present review provides an in-depth account of the current knowledge of GR-mediated transcriptional regulation of specific genes and proteins engaged in the proliferation, differentiation, and apoptosis of bone cells (osteoblasts, osteocytes, osteoclasts). We hope this knowledge will advance research in the development of SEGRAs with improved benefit/risk ratios. when bone resorption and bone formation occur on separate surfaces (i.e. formation and resorption are not coupled). An example of this process is during long bone increases in length and diameter. Bone modeling occurs from birth to adulthood and is responsible for the gain in skeletal mass and changes in skeletal form. the continuous turnover of bone matrix and mineral that involves first an increase in resorption (osteoclastic activity) and later reactive bone formation (osteoblastic activity). The bone remodeling process is conducted by osteoclasts and osteoblasts, collaborating in basic multicellular units (BMUs) and ensures the mechanical integrity of the skeleton throughout life. An imbalance in the regulation of the two contrasting events of bone resorption and bone formation results in many of the metabolic bone diseases, such as osteoporosis. an endocrine disorder caused by high levels of cortisol in the blood. This can be caused by the intake of glucocorticoid (GC) drugs or by tumors that produce cortisol, adrenocorticotropic hormone (ACTH), or corticotrophin releasing hormone (CRH). Individuals with Cushing's syndrome often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism and, in children, growth retardation. In addition to osteoporosis, hypertension, diabetes mellitus, and impaired immune function also occur. is designed to assess the feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis. growth hormone (GH) is secreted by somatotrophic cells of the anterior pituitary gland under the stimulation control of hypothalamic factor GH-releasing hormone (GHRH). GH acts directly and indirectly through insulin-like growth factor-I (IGF-I), which is the primary mediator of the effects of GH. an autoimmune arthritis seen in children, which may be either chronic or transient and self-limited. It can affect joints in any part of the body. JIA is the most common type of arthritis in childhood. a cell originating from multipotent mesenchymal stem cells, as well as from development through the process of endothelial to mesenchymal transition; osteoblasts are responsible for the synthesis of bone matrix and its mineralization. the development of osteoblasts. the development of osteoclasts. a multinucleated cell that is differentiated from hematopoietic monocyte or macrophage precursors and which is responsible for bone resorption by removing the mineralized matrix and breaking up the organic bone. Osteoclasts are characterized by high expression of the protein tartrate-resistant acid phosphatase (TRAP) and cathepsin K. a terminally differentiated osteoblast trapped within its secreted matrix. Osteocytes are networked to each other through cytoplasmic extensions and are involved in translating mechanical strain into signals of bone remodeling. a metabolic disease characterized by low bone mass and microarchitectural deterioration of bony tissue leading to enhanced bone fragility and, hence, an increase in fracture risk. Osteoporosis occurs either due to failure to achieve the peak bone mass or uncoupling of bone remodeling in which resorption exceeds formation, resulting in net bone loss.